tbuckley/cabot-search huggingface dataset:
Abstract 4172: rhIL-7-hyFc (efineptakin alpha; NT-I7) enhances the anti-tumor response when combined with anti-TIGIT or anti-VEGF
Authors: Seungtae Baek, Sun-Kyoung Im, Minji Lee, Mankyu Ji, Miyoung Kim, Kwang-Hoon Lee, Yun Hee Choi, Won Tae Kim, Donghoon Choi
Journal: Cancer Research (2022)

Abstract rhIL-7-hyFc (efineptakin-alfa; NT-I7) is a potent T cell amplifier, with a homodimeric interleukin-7 (IL-7) fused to the hybridizing IgD/IgG4 immunoglobulin domain. Previous work has shown that in mice, NT-I7 dramatically increases tumor-infiltrating CD8+ T cells while reducing the frequency of PD-1+ CD8+ T cells in the tumor. There is also significant expansion of Central Memory (CM)-phenotype CD8+ T cells (CD62L+CD44+) in the tumor and tumor draining lymph node. Here, we investigated the anti-tumor effect of NT-I7 in combination with two different T cell suppressor blockades; anti-TIGIT (YH29143) and anti-VEGF (Aflibercept) in MC38 tumor-bearing mice. NT-I7 was administered by intramuscular injection with the first dose of either YH29143 or Aflibercept. YH29143 or Aflibercept was administered every 3 days for 3 total doses, via intraperitoneal or intravenous route, respectively. The combination of NT-I7 with either T cell suppressor blockade enhanced the anti-tumor response. Surprisingly, NT-I7 combined with YH29143 increased the frequency of PD-1+TCF-1+TOX-CD39- stem-like CD8+ T cells in the draining lymph node. The combination also dramatically increased the frequency of CD62L-CD44+ effector memory CD8+ T cells in the tumor. Surprisingly, NT-I7 combined with YH29143 increased the frequency of PD-1+TCF-1+TOX-CD39- stem-like CD8+ T cells in the draining lymph node. In addition, Aflibercept reduced the expression of TOX in PD-1+ CD8+ T cells in the tumor. Our data suggests that NT-I7 can be applied in combination with other immunotherapies such as anti-TIGIT or anti-VEGF to enhance the anti-tumor response. Citation Format: Seungtae Baek, Sun-Kyoung Im, Minji Lee, Mankyu Ji, Miyoung Kim, Kwang-Hoon Lee, Yun Hee Choi, Won Tae Kim, Donghoon Choi. rhIL-7-hyFc (efineptakin alpha; NT-I7) enhances the anti-tumor response when combined with anti-TIGIT or anti-VEGF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4172.
Threat from Mycobacterium orygis-associated tuberculosis in south Asia
Authors: Jeewan Thapa, Stephen V Gordon, Chie Nakajima, Yasuhiko Suzuki
Journal: The Lancet Microbe (2022)

South Asia is a hotspot of tuberculosis with an estimated annual incidence of 3·7 million cases, accounting for 37% of the global tuberculosis incidence in 2019.1 The southeast Asia region, which includes south Asia, has a high burden from zoonotic tuberculosis, with an estimated 43 000 (31·76%) new cases in 2016; however, as the causative agent of this zoonotic tuberculosis has not been fully defined, the true incidence could be underestimated.2 Reports of tuberculosis caused by Mycobacterium orygis in animals and humans in south Asia, and the discovery of M orygis in south Asian migrants, highlights an overlooked threat from M orygis in south Asia and beyond.
Abstract 2585: Targeted protein upregulation strategy potentiates STING agonist immunotherapy
Authors: Wansang Cho, Solchan Won, Yoona Choi, Jong Beom Park, Jun-Gyu Park, Sihyeong Yi, Caroline E. Kim, Chintam Narayana, Dong-Sup Lee, Seung Bum Park
Journal: Cancer Research (2022)

Abstract As cancer immunotherapy has been emerged as a new pillar of cancer therapy, many strategies modulating host immunity were suggested for cancer treatment. Stimulator of interferon genes (STING) is a promising target for anticancer immunotherapy. However, dysregulated STING expression, or poor pharmacokinetic profiles of STING agonists pose major challenges. Recently, modulating target protein levels via the ubiquitin-proteasome system, such as proteolysis-targeting chimera (PROTAC), has broadened the scope of pharmacological inventions. Herein, we propose UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to overcome these limitations. We discovered the small molecule SB24011 that inhibits STING-E3 ligase interaction, thereby induces the blockade of E3 ligase-mediated STING degradation. As a result, SB24011 enhanced the STING agonist-mediated immune responses by upregulating cellular STING protein level. Thus, co-administration of SB24011 markedly improved the immuno-oncological efficacy of STING agonist cGAMP and anti-PD-1 therapy for tumor regression and robust systemic antitumor response. Taken together, we successfully demonstrated that targeted STING protein upregulation is a promising strategy for cancer immunotherapy. Citation Format: Wansang Cho, Solchan Won, Yoona Choi, Jong Beom Park, Jun-Gyu Park, Sihyeong Yi, Caroline E. Kim, Chintam Narayana, Dong-Sup Lee, Seung Bum Park. Targeted protein upregulation strategy potentiates STING agonist immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2585.
Osimertinib plus Selumetinib in <i>EGFR</i>-Mutated Non–Small Cell Lung Cancer After Progression on EGFR-TKIs: A Phase Ib, Open-Label, Multicenter Trial (TATTON Part B)
Authors: James Chih-Hsin Yang, Yuichiro Ohe, Chao-Hua Chiu, Xiaoling Ou, Mireille Cantarini, Pasi A. Jänne, Ryan J. Hartmaier, Myung Ju Ahn
Journal: Clinical Cancer Research (2022)

MEK/ERK inhibition can overcome acquired resistance to osimertinib in preclinical models. Osimertinib (epidermal growth factor receptor [EGFR]-tyrosine kinase inhibitor [TKI]) plus selumetinib (mitogen-activated protein kinase [MEK]1/2 inhibitor) was assessed in the global TATTON study.This multicenter, open-label, Phase 1b study expansion cohort enrolled patients (aged {greater than or equal to}18 years) with advanced MET-negative, EGFRm NSCLC who had progressed on EGFR-TKIs. Patients were assigned to one of two cohorts by prior first-/second-generation [1G/2G] or T790M-directed EGFR-TKI and received osimertinib 80 mg QD and intermittent selumetinib 75 mg BID PO. Safety and tolerability (primary objective) and antitumor activity determined by objective response rate (ORR), and progression-free survival (PFS) using RECIST version 1.1 were assessed. Data cutoff: March 4, 2020.Forty-seven patients received treatment (prior 1G/2G EGFR-TKI, n=12; prior 3G EGFR-TKI, n=35). Forty-four (94%) patients were Asian; 30 (64%) had baseline exon 19 deletion. Most common AEs were diarrhea (89%), decreased appetite (40%), and stomatitis (32%); 11/47 patients (23%) had an AE Grade {greater than or equal to}3 possibly causally selumetinib-related. ORR was 66.7% (95% confidence interval: 34.9-90.1) in the prior 1G/2G EGFR-TKI group, 22.9% (10.4-40.1) in the prior 3G EGFR-TKI group, and 34.0% (2.7-7.2) overall; median PFS was 15.0 (2.7-33.0), 2.8 (1.6-5.5), and 4.2 months (2.7-7.2), respectively.In this small study, AEs and tolerability of osimertinib plus selumetinib were as expected, based on previous studies. The combination demonstrated antitumor activity supportive of further investigation in patients with MET-negative, EGFRm advanced NSCLC, who had progressed on a previous EGFR-TKI.
Abstract 3050: Equol as a radiosensitizer and therapeutic agent in prostate cancer
Authors: Carli B. Jones, Jonathan B. Coulter, Janielle P. Maynard, Luke A. Mummert, Ryan M. Phillips, Phuoc T. Tran, Karen S. Sfanos
Journal: Cancer Research (2022)

Abstract The gastrointestinal microbiome and the metabolites it can produce have been linked to response to various cancer treatments, including in prostate cancer. Equol is a microbial metabolite that is exclusively produced by the conversion of soy isoflavones in the diet by specific intestinal bacteria. Interestingly, equol has previously been shown to exhibit anti-androgen effects on prostate cells and likewise may act as a radiosensitizer. We analyzed the microbial composition of fecal samples collected from men receiving stereotactic ablative radiation (SABR) versus observation to treat oligometastatic prostate cancer as part of the ORIOLE trial and found that patients harboring equol-producing bacteria had a lower risk of disease progression. We therefore aimed to study the effect of this compound on prostate cancer cell lines in vitro. MTT assay was used to assess the effects of equol treatment on cell viability in androgen receptor (AR) positive LNCaP cells and AR null PC3 cells over time. We assessed the ability of equol to reduce AR protein levels and/or subcellular localization in LNCaP cells using immunohistochemistry. Finally, western blotting was used to assess the effects of equol treatment on prostate specific antigen (PSA) levels to assess effects on the AR signaling pathway. Cell viability was significantly decreased over time in equol treated cells, but only in prostate cancer cell lines that were AR positive. The effects of equol on LNCaP viability was abrogated in an AR knockdown LNCaP cell line. Interestingly, AR protein levels were found to be markedly decreased upon equol treatment of LNCaP cells. We likewise observed a decrease in PSA protein levels in AR positive cells after equol treatment. Our results support the notion that equol can inhibit prostate cancer growth by inhibition of the androgen receptor. We are currently investigating whether combining equol exposure with radiation treatment produces a synergistic effect on DNA damage and reduction of prostate cancer cell viability and survival in vitro. Our future studies will investigate the effects of equol and equol-producing bacteria on tumor growth in in vivo models. Citation Format: Carli B. Jones, Jonathan B. Coulter, Janielle P. Maynard, Luke A. Mummert, Ryan M. Phillips, Phuoc T. Tran, Karen S. Sfanos. Equol as a radiosensitizer and therapeutic agent in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3050.
Abstract 2193: Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy
Authors: Jieyi Zhang, Anthony DiNatale, Ramanpreet Kaur, Qian Chen, Michael Marchioli, Darin Ipe, Maria Castelli, Christopher McNair, Gaurav Kumar, Olimpia Meucci, Alessandro Fatatis
Journal: Cancer Research (2022)

Abstract Metastasis-initiating cells (MICs) display stem cell-like features, cause metastatic recurrences and defy chemotherapy, which leads to patients’ demise. Here we show that prostate and breast cancer patients harbor contingents of tumor cells with high expression of CX3CR1, OCT4a (POU5F1) and NANOG. Impairing CX3CR1 expression or signaling hampered the formation of tumor spheroids by cell lines from which we isolated small subsets co-expressing CX3CR1 and stemness-related markers, similarly to patients’ tumors. These rare CX3CR1High cells show transcriptomic profiles enriched in pathways that regulate pluripotency and endowed with metastasis-initiating behavior in murine models. Cancer cells lacking these features (CX3CR1Low) were capable of re-acquiring CX3CR1-associated features over time, implying that MICs can continuously emerge from non-stem cancer cells. CX3CR1 expression also conferred resistance to docetaxel, and prolonged treatment with docetaxel selected CX3CR1High phenotypes with de-enriched transcriptomic profiles for apoptotic pathways. These findings nominate CX3CR1 as novel marker of stem-like tumor cells and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation. Citation Format: Jieyi Zhang, Anthony DiNatale, Ramanpreet Kaur, Qian Chen, Michael Marchioli, Darin Ipe, Maria Castelli, Christopher McNair, Gaurav Kumar, Olimpia Meucci, Alessandro Fatatis. Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2193.
Abstract 3735: Regulation of HPV gene expression by 5-azacytidine treatment in head and neck cancer
Authors: Hina Rehmani, Natalia Isaeva, Wendell G. Yarbrough
Journal: Cancer Research (2022)

Abstract Human papillomavirus (HPV) causes approximately 80% of head and neck squamous cell carcinoma (HNSCC) in the oropharynx, and its incidence is now higher than uterine cervical cancer in the US. The CDC estimates that this common sexually transmitted disease accounts for nearly 13,000 HPV+ HNSCC patients per year in the United States. Despite having a higher cure rate than HPV- HNSCC, the recurrence rate is approximately 30%. These patients have few therapeutic options since resistance to treatment arises from all known therapeutic modalities. Initial therapy for HPV+ HNSCC is aggressive and often results in negative lifelong side effects. The substantial recurrence rate and high morbidity of primary therapy suggest the need for new treatments. Global genome hypermethylation in HPV+ HNSCC, compared to HPV-, prompted our lab to explore demethylation as a therapeutic option. 5-azacytidine (5-aza) and 5-aza-2′-deoxycytidine (decitabine) are synthetic cytidine analogs that cause DNA demethylation by trapping methyltransferases to chromatin. These demethylating agents are FDA approved for the treatment of myelodysplasia and acute myeloid leukemia. Recently, we found that HPV+ HNSCC cells are more sensitive than HPV- cells to 5-aza, that low doses of 5-aza delayed HPV+ xenograft tumor growth, and that HPV+ tumor samples from patients treated with 5-aza in a window trial had increased apoptosis. We also observed a marked downregulation of HPV gene expression after 5-aza. Decreased HPV E6 expression, followed by reactivation of tumor suppressor p53, induced p53-dependent apoptosis in HPV+ HNSCC. Thus, decreased expression of HPV genes is an important component of 5-aza-associated toxicity toward HPV+ HNSCC; therefore, we further explored mechanisms through which demethylation negatively regulates the expression of HPV genes. First, we determined that 5-aza regulates transcription of HPV genes, but not the stability of HPV transcripts. Second, we found that transcriptional regulation of HPV genes after 5-aza depends on the proto-oncogene JunB, a component of the transcription factor Activator Protein 1 (AP-1). Moreover, our experiments revealed that clonogenic survival of HPV+ head and neck cancer cells is dependent on JunB expression. In summary, our study provides an improved mechanistic understanding of the regulation of HPV gene transcription in HNSCC and identifies a novel HPV+ HNSCC dependency on JunB, potentially providing a basis for a new rational targeted therapy. Citation Format: Hina Rehmani, Natalia Isaeva, Wendell G. Yarbrough. Regulation of HPV gene expression by 5-azacytidine treatment in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3735.
Abstract 1366: A novel stem cell memory T cell subpopulation intermediate to canonical stem cell memory and central memory T cells in human cancer
Authors: Daniel J. Powell
Journal: Cancer Research (2022)

Abstract Stem memory T cells (Tscm) are integral for effective immunotherapy and antitumor responses, but little is known about Tscm immunobiology in solid human tumors. Here we identify self-renewing and multipotent Tscm tumor-infiltrating lymphocytes (TILs) in human cancer and present a novel Tscm subset which expresses CD45RO, is derived from CD45RO- Tscm T cells, and is capable of self-renewal and multipotency. From the analysis of CD45RO+ Tscm differentiation, phenotyping, gene expression, and the broader TCR repertoire, we find that CD45RO+ Tscm cells are hierarchically positioned in between canonical CD45RO- Tscm cells and central memory T cells. Notably, CD45RO+ Tscm cells exhibit a gene expression profile consistent with effector capabilities and a tumor-specific phenotype that is more similar to T cells associated with successful immunotherapy than canonical Tscm. Thus, we describe a novel Tscm subset in human cancer which has distinct phenotypic, transcriptional, and effector-like attributes that position it as an attractive subset for future basic and clinical research in the setting of cancer immunotherapy. Citation Format: Daniel J. Powell. A novel stem cell memory T cell subpopulation intermediate to canonical stem cell memory and central memory T cells in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1366.
Abstract 3710: Synergistic cell death induction in ovarian cancer by cisplatin and ABT-199 is mediated by expression of NOXA
Authors: Benjamin Schaefer, Sandra Weller, Tobias B. Beigl, Klaus Schulze-Osthoff, Hans-Georg Kopp, Walter E. Aulitzky, Frank Essmann
Journal: Cancer Research (2022)

Abstract Ovarian cancer is among the top ten leading causes of cancer death in women worldwide with a mortality rate of roughly 5% among all cancer deaths. So far, there are no recommended screening tests for the early detection of ovarian cancer. Therefore, patients are frequently diagnosed at late stages of ovarian cancer, which is associated with unfavorable 5-year survival. Patients suffering from ovarian cancer often show a good response to initial therapy with platinum-based compounds and/or taxanes subsequent to resection of the affected tissue. Unfortunately, ovarian cancer shows a high frequency of relapse and after chemotherapy persistent tumor cells re-expand and successively evolve into therapy-resistant tumors. We recently reported that cisplatin (cisPt) treatment of ovarian cancer cells enhances mitochondrial content and mitochondrial reactive oxygen species (Kleih et al. 2019). We therefore speculated that the enhanced mitochondrial content primes cisPt-treated cells for apoptosis induced by BH3 mimetic drugs, such as Venetoclax (ABT-199), that act on anti-apoptotic Bcl-2 proteins at the outer mitochondrial membrane. To explore this hypothesis, we investigated whether the combined administration of cisPt and ABT-199 leads to a synergistic cell death induction in ovarian cancer cells with different cisPt resistance and mitochondrial content. Detection of cell death by flow cytometric measurements of the mitochondrial membrane potential and exposure of phosphatidylserine demonstrated a synergistic cell death induction by cisPt and ABT-199 in OVCAR4 and OVCAR8 cells, irrespective of the cisPt resistance. Interestingly, Western blot analysis revealed that ABT-199 induced the accumulation of the BH3-only protein NOXA in both cancer cell lines. Accumulation of NOXA was dependent on ABT-199-mediated activation of the stress-responsive transcription factor ATF4. Knock-down experiments showed that apoptosis of cisPt-resistant OVCAR8 cells by the combined treatment with ABT-199 and cisPt was entirely dependent on NOXA. Moreover, also cisPt-sensitive OVCAR4 cells revealed an initially reduced apoptosis induction by the NOXA knock-down. Our data therefore elucidate the molecular mechanism of the synergistic efficacy of cisPt/ABT-199 combination therapies, which should be promising especially for the treatment of recurrent tumors developing reduced sensitivity to cisPt-based treatments. Citation Format: Benjamin Schaefer, Sandra Weller, Tobias B. Beigl, Klaus Schulze-Osthoff, Hans-Georg Kopp, Walter E. Aulitzky, Frank Essmann. Synergistic cell death induction in ovarian cancer by cisplatin and ABT-199 is mediated by expression of NOXA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3710.
Abstract 1454: Interaction of obesity loci with energy intake and physical activity on the risk of colorectal cancer: Evidence from UK Biobank
Authors: Sooyoung Cho, Aesun Shin
Journal: Cancer Research (2022)

Abstract Colorectal cancer is one of the common cancers worldwide. Obesity and physical activity are well-established risk factors for colorectal cancer. Studies have shown that as a consequence of energy metabolism, imbalance between energy intake and physical activity can lead to obesity. In order to precisely examine the close interrelationship between obesity, energy intake, and physical activity, we conducted a genome-wide interaction study of obesity with energy intake and physical activity. We also evaluated the interaction between obesity susceptibility loci with energy intake and physical activity for colorectal cancer using the nested case-control design. We analyzed data on participants in the UK Biobank. Genome-wide interaction analyses of obesity with energy intake and physical activity was performed on 65,514 and 250,369 participants who have information on genotype, body mass index, and energy intake/physical activity, respectively. We assessed the effect of obesity loci in the participants comprised 3523 colorectal cancer cases and 10,522 matched controls. The logistic regression model was used for finding obesity loci under a p-value threshold of 10-4. Odds ratios (ORs) and 95% confidence intervals (CIs) for colorectal cancer were estimated using a conditional logistic regression model. We found 21 loci and 44 loci of obesity with energy intake and physical activity, respectively. We also observed significant interaction of obesity loci with energy intake and physical activity for colorectal cancer. The obesity loci interacting with energy intake, including rs10828896 and rs7099260, were significantly interacted with physical activity for colorectal cancer. Rs426345 and rs12551684, which were the obesity loci interacting with physical activity, were significantly interacted with energy intake for colorectal cancer. The results of this study may provide evidence for bioenergetics in colorectal cancer carcinogenesis. Citation Format: Sooyoung Cho, Aesun Shin. Interaction of obesity loci with energy intake and physical activity on the risk of colorectal cancer: Evidence from UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1454.